Genetic control of autoimmunity to acetylcholine receptors: role of Ia molecules.
Evidence that human susceptibility to myasthenia gravis (MG) might be determined genetically is suggested by clinical surveys showing an association of MG with an increased frequency of certain histocompatibility antigens. We have studied the experimental autoimmune model of MG in mice to investigate whether or not major histocompatibility complex (MHC) gene products play a role in determining susceptibility to EAMG. When MHC congenic and recombinant strains of mice were inoculated with Torpedo acetylcholine receptor (AChR) and adjuvants, the magnitude of autoantibody responses to muscle AChR and of the defect of neuromuscular transmission (i.e., reduction in MEPP amplitude) closely paralleled in vitro lymphocyte proliferative responses to torpedo AChR. Reduction in MEPP amplitude correlated strikingly with the degree to which autologous muscle AChR was complexed with antibody. Lymphocyte responses to Torpedo AChR, antibody responses to mouse muscle AChR, and susceptibility to EAMG are controlled by gene(s) at the I-A subregion of the H-2 complex. Backcross studies confirmed that lymphocyte proliferative responses to AChR are controlled by a Mendelian dominant gene linked to H-2, probably at the I-A subregion. Mutation at the I-A subregion in the B6 strain, which resulted in structural alteration of the Ia molecule, converted high responsiveness to low responsiveness. Lymphocyte responses were eliminated by blocking Ia antigens on lymph node cell surfaces with specific anti-I-A alloantisera. Cellular immune responses to AChR are dependent on Lyt 1+23- cells and adherent cells. These data implicate a macrophage-associated Ia molecular in induction of autoimmune responses to AChR, probably in the presentation of AChR to helper (Lyt 1+23-) T-lymphocytes, which thereby help B-lymphocytes to differentiate into anti-AChR antibody forming cells.
D000200:Action Potentials; D000818:Animals; D001323:Autoantibodies / Q000032:analysis*; D005802:Genes, MHC Class II; D006183:H-2 Antigens / Q000235:genetics; D006238:Haploidy; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex; D051379:Mice; D008815:Mice, Inbred Strains; D009157:Myasthenia Gravis / Q000276:immunology*; D009469:Neuromuscular Junction / Q000502:physiology; D011950:Receptors, Cholinergic / Q000235:genetics / Q000276:immunology*
D001323:Autoantibodies; D006183:H-2 Antigens; D000949:Histocompatibility Antigens Class II; D011950:Receptors, Cholinergic